WO2023055079A1 - Composition for preventing, alleviating or treating metabolic syndrome, comprising carob extract - Google Patents

Composition for preventing, alleviating or treating metabolic syndrome, comprising carob extract Download PDF

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WO2023055079A1
WO2023055079A1 PCT/KR2022/014570 KR2022014570W WO2023055079A1 WO 2023055079 A1 WO2023055079 A1 WO 2023055079A1 KR 2022014570 W KR2022014570 W KR 2022014570W WO 2023055079 A1 WO2023055079 A1 WO 2023055079A1
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composition
carob
extract
composition according
carob extract
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French (fr)
Korean (ko)
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최범락
구세광
박혜림
이현
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주식회사 뉴트라코어
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/332—Promoters of weight control and weight loss
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2300/00—Processes
    • A23V2300/14—Extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH

Definitions

  • the present invention relates to a composition for preventing, improving or treating metabolic syndrome such as obesity, diabetes, hyperlipidemia and fatty liver, comprising a natural extract as an active ingredient.
  • Obesity is a cause of various lethal metabolic diseases such as cardiovascular disease, hypertension, and Type II diabetes.
  • fat cells When obese, fat cells not only store lipids as a long-term energy source, but also play a variety of roles involved in metabolism and inflammation of fat cells and non-adipocytes. They secrete adipokines to induce chronic inflammation and related metabolic diseases such as insulin resistance.
  • Type II diabetes the incidence of metabolic syndrome known as Type II diabetes is increasing worldwide due to obesity due to lack of exercise along with high-calorie diet, and by 2025, the number of patients with metabolic syndrome will double, that is, approximately 300 million people. It is predicted to come close.
  • Obesity caused by abnormal local fat accumulation such as abdominal obesity, provides various causes that can seriously induce arterial atheropathy, such as hypertension, hyperlipidemia, blood clotting disorders, vascular inflammation, and insulin resistance accompanied by abnormal insulin secretion. Finally, it is a factor in the increased prevalence of fatal cardiovascular diseases. Excessive intake of fatty acids causes accumulation of triglyceride (TG) in various tissues, which accompanies an increase in lipolysis and at the same time causes an increase in circulating fatty acids in the blood, and induces insulin resistance in fat cells, resulting in muscle and pancreas and fat accumulation in non-adipocytes such as liver.
  • TG triglyceride
  • TG in hepatocytes also causes non-alcoholic fatty liver disease (NAFLD), and causes fat accumulation in liver cells mainly responsible for glucose metabolism, resulting in steatohepatitis secondary. , finally causing fibrosis by necrosis of hepatocytes. Therefore, the balance of fat synthesis and degradation in hepatocytes has been an important therapeutic target that can suppress the induction of insulin resistance and NAFLD caused by metabolic syndrome.
  • NAFLD non-alcoholic fatty liver disease
  • metformin is a representative oral biguanide-based antidiabetic treatment and is well known as an AMPK activator.
  • Metformin is the first drug used to treat overweight and obese type II diabetic patients with normal kidney function. It is known as the only drug capable of controlling the secretion of pancreatic enzyme granules and the activity of enzymes related to liver sugar metabolism. Metformin is currently known as the most prescribed diabetes treatment worldwide. Metformin is mainly used as a treatment for type II diabetes, but prescriptions for polycystic ovary syndrome and premature puberty are also increasing. On the other hand, side effects such as lactic acidosis caused by metformin are well known.
  • the present inventors have researched to develop a natural product that has no side effects while exhibiting the effect of treating and suppressing metabolic syndrome such as obesity, diabetes, hyperlipidemia and fatty liver. As a result, carob extract has a remarkable effect in preventing, improving, and treating metabolic syndrome. By finding out, the present invention was completed.
  • an object of the present invention is to provide the following embodiments.
  • Embodiment 1 A composition for preventing, improving or treating at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, containing carob extract as an active ingredient; A method for preventing, improving or treating at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, comprising administering a carob extract to a subject in need thereof; Or use of a carob extract for the manufacture of medicines, products, foods or health functional foods for the prevention, improvement or treatment of at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver.
  • Embodiment 2 The composition according to embodiment 1, wherein the carob extract contains apigenin, syringic acid and/or pinitol as active ingredients; method; or use.
  • Embodiment 3 The composition according to any one of the preceding embodiments, wherein the carob extract comprises syringic acid in an amount of 40 ⁇ g/g to 200 ⁇ g/g; method; or use.
  • Embodiment 4 The composition according to any one of the preceding embodiments, wherein the carob extract comprises pinitol and syringic acid in a weight ratio of 200 to 500: 1 (pinitol: syringic acid). ; method; or use.
  • Embodiment 5 The composition according to any one of the preceding embodiments, wherein the carob extract is a carob fruit extract; method; or use.
  • Embodiment 6 The carob extract according to any one of the preceding embodiments, wherein the carob extract is extracted using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent. composition to; method; or use.
  • Embodiment 7 The composition according to any one of the preceding embodiments, wherein the composition or the carob extract has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction, and fatty liver improvement. ; method; or use.
  • Embodiment 8 The method according to any one of the preceding embodiments, wherein the composition or the carob extract has at least one effect selected from the group consisting of weight loss, body fat reduction, and abdominal fat reduction without causing a decrease in appetite. characterized composition; method; or use.
  • Embodiment 9 The composition according to any one of the preceding embodiments, wherein the composition is a food composition; method; or use.
  • Embodiment 10 The composition according to any one of the preceding embodiments, wherein the composition is a pharmaceutical composition.
  • Embodiment 11 A health functional food comprising the composition or carob extract as defined in any one of the preceding embodiments.
  • Embodiment 12 Grinding carob raw materials; And a composition defined in any one of the preceding embodiments comprising the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent, or Method for producing carob extract.
  • One aspect of the present invention is a composition for the prevention, improvement or treatment of at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, comprising a carob extract as an active ingredient, It is to provide a composition that does.
  • Carob Ceratonia siliqua (L.) Taub
  • Ceratonia siliqua (L.) Taub) is a bean-shaped fruit of Ceratonia siliqua, which is native to the Mediterranean coast, and is known to be native to parts of the United States and Australia. It is known that kerob contains very high tannin and causes specific astringency, so its edibleness is extremely limited.
  • composition of the present invention includes carob extract as an active ingredient, and the term 'extract' used herein refers to an extraction result obtained by extracting the original material or treating the original material with an extraction solvent, or formulating (eg, powdering) the raw material. It also has a meaning including processed products.
  • the polar solvent includes (i) water, (ii) alcohol (preferably methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene).
  • non-polar solvents include acetone, acetonitrile, ethyl acetate, methyl acetate, Alkanes, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl Ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrach
  • the extract used in the present invention may be extracted by squeezing raw material or using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent, but this is not limited to
  • the extract of the present invention may be obtained by performing an additional process, such as filtration, concentration or drying, to remove the solvent, or filtration, concentration, and drying.
  • an additional process such as filtration, concentration or drying, to remove the solvent, or filtration, concentration, and drying.
  • concentration may be performed with a vacuum concentrator
  • drying may be performed by spray drying or freeze drying to obtain a powdery extract.
  • carob extract can be obtained by grinding carob raw materials, for example, carob fruit; And it can be prepared by a method comprising the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
  • the carob extract prepared as above may contain apigenin, syringic acid and pinitol as active ingredients.
  • the carob extract of the present invention contains at least one selected from the group consisting of obesity, diabetes, hyperlipidemia, and fatty liver without reducing appetite due to the inclusion of apigenin, syringic acid, and pinitol. It has been confirmed to have preventive, ameliorative or therapeutic effects on metabolic syndrome.
  • the carob extract of the present invention may contain syringic acid in an amount of 40 ⁇ g/g to 200 ⁇ g/g. More specifically, the content of syringinic acid is 40 ⁇ g / g, 50 ⁇ g / g, 60 ⁇ g / g, 70 ⁇ g / g, 80 ⁇ g / g, 90 ⁇ g / g, 100 ⁇ g / g, 110 ⁇ g / g, 120 ⁇ g/g, 130 ⁇ g/g, 140 ⁇ g/g, 150 ⁇ g/g, 160 ⁇ g/g, 170 ⁇ g/g, 180 ⁇ g/g, 190 ⁇ g/g or 200 ⁇ g/g, but is limited thereto It is not, and may be included in any amount in the range of 40 ⁇ g / g to 200 ⁇ g / g.
  • the carob extract of the present invention may include pinitol and syringic acid in a weight ratio of 200 to 500: 1 (pinitol: syringic acid).
  • pinitol and syringin acid in the carob extract may have a synergistic effect compared to the case where they are included in other weight ratios.
  • the weight ratio of pinitol to syringinic acid contained in the carob extract may be, but is not limited to, 200:1, 300:1, 400:1 or 500:1, and any range in the range of 200 to 500:1 may be included in a weight ratio of
  • the composition of the present invention comprises the steps of grinding carob raw materials; And it can be prepared by including the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
  • composition of the present invention does not cause appetite reduction, and at least one metabolism selected from the group consisting of obesity, diabetes, hyperlipidemia, and fatty liver It can show preventive, ameliorative or therapeutic effects of metabolic syndrome.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic syndrome formulated in a pharmaceutical unit dosage form by adding a pharmaceutically acceptable carrier, excipient or diluent, including a composition containing the active ingredient. .
  • pharmaceutically acceptable means a non-toxic composition that is physiologically acceptable and does not inhibit the action of the active ingredient when administered to humans and does not usually cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions. says
  • the carrier, excipient or diluent examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose. , polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers or preservatives.
  • pharmaceutically effective amount refers to an amount that exhibits a greater response than that of the negative control group, and preferably refers to an amount sufficient to exhibit the effect of preventing and/or treating metabolic syndrome.
  • the pharmaceutical composition of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the dosage form may be in the form of a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, or sterile powder.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but may be administered orally or parenterally.
  • Parenteral routes of administration may include, for example, various routes such as transdermal, intranasal, intraperitoneal, intramuscular, subcutaneous or intravenous routes.
  • the pharmaceutical composition of the present invention can be administered in parallel with known compounds having preventive and/or therapeutic effects on metabolic syndrome.
  • the present invention provides a food composition comprising any one of the above compositions.
  • the food composition of the present invention includes processed forms of all natural materials such as food, functional food, nutritional supplement, health feed and food additives.
  • Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
  • carob extract itself can be prepared in the form of tea, juice and drink to be consumed, or granulated, encapsulated, or powdered to be consumed.
  • composition of the present invention has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction and fatty liver improvement, thereby exhibiting an effect of preventing, improving or treating metabolic syndrome.
  • Figure 2 shows the results of evaluating the change in mouse weight in order to verify the anti-obesity effect.
  • Figure 3 shows the experimental results of changes in mouse body fat and abdominal fat to verify the anti-obesity effect.
  • Figure 4 shows the results of measuring cholesterol and neutral lipid excretion through mouse feces.
  • Figure 6 shows the results of measuring the area where steatohepatitis occurred in mouse liver tissue (hepatic parenchyma).
  • the carob extract contained apigenin, syringic acid and pinitol.
  • mice which are rodents
  • HFD high fat diet
  • mice a total of 200 6-week-old female ICR mice [OrientBio, Seungnam, Korea] were acclimatized to the laboratory environment for 7 days and then to HFD for 1 week. All experimental animals were treated according to the animal experimentation ethics standards under the prior approval of the Laboratory Animal Ethics Committee of Daegu Haany University. In the normal control group, NFD (Normal Fat Diet) was supplied in the same way.
  • the carob extract (CR) prepared above was used as a test substance.
  • the dose of the test substance was set at 200 mg/kg.
  • the carob extract was dissolved in sterile distilled water at a concentration of 20 mg/ml, and forced orally once daily for 84 days at 10 ml/kg, which is the normal oral administration volume of mice. administered.
  • metformin used as a control drug was set at 250 mg/kg based on previous references. Metformin was also dissolved in sterile distilled water at a concentration of 25 mg/ml and then orally administered at a dose of 10 ml/kg (250 mg/kg) once daily for 84 days.
  • the HFD control group showed a significant increase during the 1-week HFD adaptation period compared to the normal control group (NFD), and showed a significant increase in body weight during the 84-day test material administration period.
  • metformin 250 mg/kg (positive control group) and carob extract 200 mg/kg (test group) were administered, significant weight loss was observed compared to the HFD control group.
  • the 200 mg/kg administration group in the carob extract was confirmed to have excellent hyperlipidemia-improving activity in both blood cholesterol and neutral lipids, LDL & HDL cholesterol levels.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • GTT gamma-glutamyltransferase
  • Nonalcoholic fatty liver disease in which triglyceride (TG) is excessively accumulated in the liver, is associated with metabolic syndrome such as obesity, insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia. It may also accompany liver steatohepatitis.
  • the mouse was sacrificed and the area where steatohepatitis occurred in the mouse liver tissue (hepatic parenchyma) was measured through a histological examination, and the results are shown in FIG. 6 .
  • the area where steatohepatitis occurred in the mouse liver tissue was measured through a histological examination, and the results are shown in FIG. 6 .
  • significantly higher steatohepatitis was observed in the HFD control group than in the normal control group.
  • the group administered with 250 mg/kg of metformin and 200 mg/kg of carob extract it was confirmed to have a fatty liver improving activity by showing significant improvement in steatohepatitis compared to the HFD control group (FIG. 6).
  • the differentiation inhibitory activity of 3T3-L1 preadipocytes was measured after treatment with the test substance.
  • metformin was used, and as an experimental substance, pinitol was added to the carob extract (CR) prepared in Example I to adjust the weight ratio of pinitol and syringin acid contained in the carob extract as shown in Table 3 below. .
  • the treatment capacity of each test substance was equally set at 100 ⁇ g/ml.
  • sample processing capacity control 100 ⁇ g/ml pinitol 100 ⁇ g/ml syringic acid 100 ⁇ g/ml CR - carob extract prepared in Example I above 100 ⁇ g/ml CR (100:1) - carob extract adjusted to a pinitol:syringic acid weight ratio of 100:1 100 ⁇ g/ml CR(200:1) - carob extract adjusted to pinitol:syringic acid weight ratio of 200:1 100 ⁇ g/ml CR(500:1) - carob extract adjusted to pinitol:syringic acid weight ratio of 500:1 100 ⁇ g/ml CR(1000:1) - carob extract adjusted to 1000:1 weight ratio of pinitol:syringic acid 100 ⁇ g/ml
  • Dulbecco's modified Eagle's medium high glucose (DMEM: Invitrogen, Carlsbad, CA, USA) was added with 10% calf serum and antibiotics, and cultured in a 5% CO 2 , 37°C incubator so that the cells were confluent. After treatment with trypsin/EDTA, the cells are centrifuged (L-70, Bekman Coulter, Fullerton, CA, USA) to collect the cells and dispensed into 6 wells at a density of 3 ⁇ 10 5 cells/well for 48 hours at 100% confluency. After standing, DMEM contained 10% BCS, 23 mg/mL IBMX (Sigma-Aldrich, Chem. Co., St.
  • the test substance was treated at a concentration of 100 ⁇ g/ml from the time of addition of the differentiation induction medium, and after differentiation for 9 days, the medium was removed, washed with phosphate buffered saline (PBS), and cells were fixed with 10% formaldehyde solution. .
  • PBS phosphate buffered saline

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Abstract

The present invention relates to a composition for preventing, alleviating, or treating metabolic syndromes such as obesity, diabetes, hyperlipidemia, and fatty liver, comprising, as an active ingredient, a carob extract, which is a natural extract.　

Description

캐롭 추출물을 포함하는 대사증후군의 예방, 개선 또는 치료용 조성물Composition for preventing, improving or treating metabolic syndrome containing carob extract
본 출원은 2021년 10월 1일 출원된 대한민국출원 제 10-2021-0131191호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application claims priority based on Korean Application No. 10-2021-0131191 filed on October 1, 2021, and all contents disclosed in the specification and drawings of the application are incorporated into this application.
본 발명은 천연 추출물을 유효성분으로 포함하는, 비만, 당뇨, 고지혈증 및 지방간과 같은 대사증후군의 예방, 개선 또는 치료용 조성물에 관한 것이다.　The present invention relates to a composition for preventing, improving or treating metabolic syndrome such as obesity, diabetes, hyperlipidemia and fatty liver, comprising a natural extract as an active ingredient.
비만은 심혈관계질환, 고혈압 및 Type II 당뇨병과 같은 다양한 치사성 대사 질환의 원인으로, 비만시 지방세포는 장기형 에너지원으로 지질을 저장할 뿐만 아니라 지방세포 및 비지방세포의 대사와 염증에 관여하는 다양한 adipokine을 분비하여 만성 염증을 유발하고, 인슐린 저항성과 같은 관련 대사성 질환을 야기한다. 최근에 들어, 전세계적으로 고열량의 식이와 함께 운동 부족으로 인한 비만으로 Type II 당뇨병으로 알려진 대사 증후군의 발병 증가가 일어나고 있으며, 2025년에는 대사성 증후군 환자가 현재의 2배 즉, 대략 3억 명에 육박할 것으로 예측되고 있다. 복부 비만과 같이 비정상적인 국소 지방 축적에 의한 비만은 고혈압, 고지혈증, 혈액 응고 장애, 혈관 염증, 비정상적인 인슐린 분비증가를 동반한 인슐린 저항성과 같은 동맥 죽종상 병증을 심각하게 유발할 수 있는 다양한 원인을 제공하고, 최종적으로 치사적인 심혈관계 질환에 대한 유병율 증가의 요인이 된다. 지방산의 과다한 섭취는 다양한 조직에서 triglyceride (TG)의 축적을 유발하여, 지방분해의 증가를 수반함과 동시에 혈중 순환 지방산의 증가를 초래하고, 지방세포에서 인슐린 저항성을 유발하여, 결과적으로 근육, 췌장 및 간과 같은 비지방세포에서 지방 축적을 일으킨다. 지방세포에서 인슐린 저항성이 유발되면, 잉여의 지방산 결합 및 운반 단백질이 비지방세포의 지방산 흡수 증가를 초래하고, 특히 근육세포의 경우 인슐린 매개성 포도당 대사에 악영향을 미치며, 이와 동시에 췌장에서는, 유리 지방산에 장기간 노출되어, 소위 지방독성 (lipotoxicity) 기전에 의해 인슐린 분비 장애가 초래되는 악순환이 반복된다. 이 경우, 간에서도 고농도의 유리지방산이 축적되어, 인슐린에 대한 저항성이 초래되고, 다량의 포도당을 간에서부터 유리시키기 시작한다. 간세포 내 TG 의 축적은 또한 비알코올성 간 지방병증(non-alcoholic fatty liver disease; NAFLD)을 유발하며, 포도당 대사를 주로 담당하는 간 세포의 지방축적을 유발 하여, 지방간염(steatohepatitis)을 이차적으로 일으키고, 최종적으로 간세포의 괴사에 의 한 섬유화를 유발한다. 따라서 간세포의 지방 합성과 분해의 균형은 대사 증후군 시 초래되는 인슐린 저항성과 NAFLD의 유발을 억제할 수 있는 중요한 치료 표적이 되어왔다. Obesity is a cause of various lethal metabolic diseases such as cardiovascular disease, hypertension, and Type II diabetes. When obese, fat cells not only store lipids as a long-term energy source, but also play a variety of roles involved in metabolism and inflammation of fat cells and non-adipocytes. They secrete adipokines to induce chronic inflammation and related metabolic diseases such as insulin resistance. In recent years, the incidence of metabolic syndrome known as Type II diabetes is increasing worldwide due to obesity due to lack of exercise along with high-calorie diet, and by 2025, the number of patients with metabolic syndrome will double, that is, approximately 300 million people. It is predicted to come close. Obesity caused by abnormal local fat accumulation, such as abdominal obesity, provides various causes that can seriously induce arterial atheropathy, such as hypertension, hyperlipidemia, blood clotting disorders, vascular inflammation, and insulin resistance accompanied by abnormal insulin secretion. Finally, it is a factor in the increased prevalence of fatal cardiovascular diseases. Excessive intake of fatty acids causes accumulation of triglyceride (TG) in various tissues, which accompanies an increase in lipolysis and at the same time causes an increase in circulating fatty acids in the blood, and induces insulin resistance in fat cells, resulting in muscle and pancreas and fat accumulation in non-adipocytes such as liver. When insulin resistance is induced in adipocytes, excess fatty acid binding and transport proteins cause increased fatty acid absorption in non-adipocytes, adversely affecting insulin-mediated glucose metabolism, especially in muscle cells, and at the same time, in pancreas, free fatty acids is exposed for a long time, a vicious cycle in which insulin secretion disorder is caused by a so-called lipotoxicity mechanism is repeated. In this case, high-concentration free fatty acids are also accumulated in the liver, resulting in resistance to insulin, and a large amount of glucose begins to be released from the liver. Accumulation of TG in hepatocytes also causes non-alcoholic fatty liver disease (NAFLD), and causes fat accumulation in liver cells mainly responsible for glucose metabolism, resulting in steatohepatitis secondary. , finally causing fibrosis by necrosis of hepatocytes. Therefore, the balance of fat synthesis and degradation in hepatocytes has been an important therapeutic target that can suppress the induction of insulin resistance and NAFLD caused by metabolic syndrome.
현재 다양한 대사증후군 치료제들이 개발되어 있으며, 근래에 들어 적절한 혈당 조절과 함께 당뇨 및 관련 합병증의 주요 병인으로 지목 되고 있는 산화 스트레스의 적절한 제어가 당뇨 치료에 가장 핵심적인 방법으로 부각됨에 따라, 부작용이 낮고 보다 효과적인 α-glucosidase 차단제 또는 항산화제들의 개발이 시도되고 있다.Currently, various metabolic syndrome treatments are being developed, and in recent years, appropriate control of oxidative stress, which has been pointed out as a major cause of diabetes and related complications along with appropriate blood sugar control, has emerged as the most important method for diabetes treatment, resulting in low side effects and low side effects. Development of more effective α-glucosidase blockers or antioxidants is being attempted.
이들 중 metformin은 대표적인 경구용 biguanide 계열 항당뇨 치 료제로 AMPK activator로 잘 알려져 있다. Metformin은 신장 기능이 정상적인 과 체중 및 비만 type II 당뇨병 환자를 치료하기 위해 가장 먼저 사용되는 약물이며, 당뇨병에 의한 심각한 부작용 중 하나인 심혈관계 질환 발병을 낮출 수 있고, 지방의 소화 분해에 직접 관여하는 췌장의 효소원 과립의 분비 및 간 당대사 관련 효소의 활성을 조절할 수 있는 유일한 약물로 알려져 있다. Metformin 은 현재 전세계적으로 가장 많이 처방되는 당뇨치료제로 알려져 있다. Metformin 은 주로 type II 당뇨병 치료제로 사용되나, 다낭성 난소 증후군(polycystic ovary syndrome) 및 성조숙 (premature puberty)에 대한 처방 역시 증가되고 있는 추세이다. 한편, metformin 은 신장 장애에 따른 lactic acidosis 와 같은 부작용 역시 잘 알려져 있다.Among them, metformin is a representative oral biguanide-based antidiabetic treatment and is well known as an AMPK activator. Metformin is the first drug used to treat overweight and obese type II diabetic patients with normal kidney function. It is known as the only drug capable of controlling the secretion of pancreatic enzyme granules and the activity of enzymes related to liver sugar metabolism. Metformin is currently known as the most prescribed diabetes treatment worldwide. Metformin is mainly used as a treatment for type II diabetes, but prescriptions for polycystic ovary syndrome and premature puberty are also increasing. On the other hand, side effects such as lactic acidosis caused by metformin are well known.
그리하여, 부작용이 낮고 보다 효과적인 천연물 유래의 대체 건강기능식품 및 의약품의 개발이 요구되고 있는 실정이다. Therefore, there is a demand for the development of alternative health functional foods and pharmaceuticals derived from natural products that have low side effects and are more effective.
본 명세서 전체에 걸쳐 다수의 문헌이 참조되고 그 인용이 표시되어 있다. 인용된 문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다. A number of documents are referenced throughout this specification and citations are indicated. The disclosure contents of the cited documents are incorporated herein by reference in their entirety to more clearly describe the content of the present invention and the level of the technical field to which the present invention belongs.
본 발명자들은 비만, 당뇨, 고지혈증 및 지방간과 같은 대사증후군의 치료 및 억제의 효과를 나타내면서 부작용이 없는 천연물을 개발하고자 연구 노력한 결과, 캐롭 추출물이 대사증후군의 예방, 개선 및 치료에 있어서 현저한 효과가 있음을 밝혀냄으로써, 본 발명을 완성하게 되었다. The present inventors have researched to develop a natural product that has no side effects while exhibiting the effect of treating and suppressing metabolic syndrome such as obesity, diabetes, hyperlipidemia and fatty liver. As a result, carob extract has a remarkable effect in preventing, improving, and treating metabolic syndrome. By finding out, the present invention was completed.
따라서 본 발명의 목적은 다음의 구현예들을 제공하는 데 있다. Accordingly, an object of the present invention is to provide the following embodiments.
구현예 1. 캐롭 추출물을 유효성분으로 포함하는, 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료를 위한 조성물; 이를 필요로 하는 대상체에게 캐롭 추출물을 투여하는 것을 포함하는, 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료를 위한 방법; 또는 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료를 위한 의약품, 제품, 식품 또는 건강기능식품 제조를 위한, 캐롭 추출물의 용도. Embodiment 1. A composition for preventing, improving or treating at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, containing carob extract as an active ingredient; A method for preventing, improving or treating at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, comprising administering a carob extract to a subject in need thereof; Or use of a carob extract for the manufacture of medicines, products, foods or health functional foods for the prevention, improvement or treatment of at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver.
구현예 2. 구현예 1에 있어서, 상기 캐롭 추출물은 아피제닌(apigenin), 시린진산(syringic acid) 및/또는 피니톨(pinitol)을 유효성분으로 포함하는 것인 조성물; 방법; 또는 용도. Embodiment 2. The composition according to embodiment 1, wherein the carob extract contains apigenin, syringic acid and/or pinitol as active ingredients; method; or use.
구현예 3. 선행하는 구현예들 중 어느 하나에 있어서, 상기 캐롭 추출물은 시린진산(syringic acid)을 40 μg/g 내지 200 μg/g의 함량으로 포함하는 것인 조성물; 방법; 또는 용도. Embodiment 3. The composition according to any one of the preceding embodiments, wherein the carob extract comprises syringic acid in an amount of 40 μg/g to 200 μg/g; method; or use.
구현예 4. 선행하는 구현예들 중 어느 하나에 있어서, 상기 캐롭 추출물은 피니톨(pinitol) 및 시린진산(syringic acid)을 200~500:1 (피니톨:시린진산)의 중량비로 포함하는 것인 조성물; 방법; 또는 용도.Embodiment 4. The composition according to any one of the preceding embodiments, wherein the carob extract comprises pinitol and syringic acid in a weight ratio of 200 to 500: 1 (pinitol: syringic acid). ; method; or use.
구현예 5. 선행하는 구현예들 중 어느 하나에 있어서, 상기 캐롭 추출물은 캐롭 열매 추출물인 것을 특징으로 하는 조성물; 방법; 또는 용도. Embodiment 5. The composition according to any one of the preceding embodiments, wherein the carob extract is a carob fruit extract; method; or use.
구현예 6. 선행하는 구현예들 중 어느 하나에 있어서, 상기 캐롭 추출물은 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출한 것을 특징으로 하는 조성물; 방법; 또는 용도. Embodiment 6. The carob extract according to any one of the preceding embodiments, wherein the carob extract is extracted using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent. composition to; method; or use.
구현예 7. 선행하는 구현예들 중 어느 하나에 있어서, 상기 조성물 또는 상기 캐롭 추출물은 체중감소, 혈당감소, 혈중 지질감소 및 지방간 개선으로 이루어진 군으로부터 선택되는 1 이상의 효과를 갖는 것을 특징으로 하는 조성물; 방법; 또는 용도. Embodiment 7. The composition according to any one of the preceding embodiments, wherein the composition or the carob extract has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction, and fatty liver improvement. ; method; or use.
구현예 8. 선행하는 구현예들 중 어느 하나에 있어서, 상기 조성물 또는 상기 캐롭 추출물은 식욕 감소를 일으키지 않으면서, 체중감소, 체지방 감소 및 복부 지방 감소로 이루어진 군으로부터 선택되는 1 이상의 효과를 갖는 것을 특징으로 하는 조성물; 방법; 또는 용도.Embodiment 8. The method according to any one of the preceding embodiments, wherein the composition or the carob extract has at least one effect selected from the group consisting of weight loss, body fat reduction, and abdominal fat reduction without causing a decrease in appetite. characterized composition; method; or use.
구현예 9. 선행하는 구현예들 중 어느 하나에 있어서, 상기 조성물은 식품 조성물인 것을 특징으로 하는 조성물; 방법; 또는 용도.Embodiment 9. The composition according to any one of the preceding embodiments, wherein the composition is a food composition; method; or use.
구현예 10. 선행하는 구현예들 중 어느 하나에 있어서, 상기 조성물은 약학 조성물인 것을 특징으로 하는 조성물. Embodiment 10. The composition according to any one of the preceding embodiments, wherein the composition is a pharmaceutical composition.
구현예 11. 선행하는 구현예들 중 어느 하나에 정의된 조성물 또는 캐롭 추출물을 포함하는 건강기능식품.Embodiment 11. A health functional food comprising the composition or carob extract as defined in any one of the preceding embodiments.
구현예 12. 캐롭 원료를 분쇄하는 단계; 및 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출 공정을 수행하는 단계를 포함하는 선행하는 구현예들 중 어느 하나에 정의된 조성물 또는 캐롭 추출물의 제조방법.Embodiment 12. Grinding carob raw materials; And a composition defined in any one of the preceding embodiments comprising the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent, or Method for producing carob extract.
본 발명의 또 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다. Further objects and advantages of the present invention will become more apparent from the following detailed description, claims and drawings.
본 발명의 하나의 관점은 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료를 위한 조성물로서, 캐롭 추출물을 유효성분으로 포함하는 것을 특징으로 하는 조성물을 제공하는 것이다. One aspect of the present invention is a composition for the prevention, improvement or treatment of at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, comprising a carob extract as an active ingredient, It is to provide a composition that does.
캐롭(Carob, Ceratonia siliqua (L.) Taub)은 지중해 연안에 자생하는 Ceratonia siliqua 의 콩모양 열매로, 미국 및 호주의 일부 지역에서도 자생하는 것으로 알려져 있다. 케롭은 매우 높은 tannin 을 함유하여, 특이한 자극성 (astringency)를 유발하므로, 식용이 극히 제한되는 것으로 알려져 있다.Carob ( Ceratonia siliqua (L.) Taub) is a bean-shaped fruit of Ceratonia siliqua, which is native to the Mediterranean coast, and is known to be native to parts of the United States and Australia. It is known that kerob contains very high tannin and causes specific astringency, so its edibleness is extremely limited.
본 발명의 조성물은 유효성분으로서 캐롭 추출물을 포함하는데, 본 명세서에서 사용되는 용어 '추출물'은 원물을 착즙, 또는 원물에 추출용매를 처리하여 얻은 추출 결과물이나 이를 제형화(예컨대, 분말화)한 가공물도 포함하는 의미를 갖는다.The composition of the present invention includes carob extract as an active ingredient, and the term 'extract' used herein refers to an extraction result obtained by extracting the original material or treating the original material with an extraction solvent, or formulating (eg, powdering) the raw material. It also has a meaning including processed products.
본 발명의 조성물에서 이용되는 추출물을 원물에 추출용매를 처리하여 얻는 경우에는, 다양한 추출용매가 이용될 수 있는데 예컨대, 극성 용매 또는 비극성 용매를 이용할 수 있다. 극성 용매로는 (i) 물, (ii) 알코올(바람직하게는, 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올 또는 에틸렌글리콜), (iii) 아세트산, (iv) DMF(dimethyl-formamide) 및 (v) DMSO(dimethyl sulfoxide) 등을 사용할 수 있고, 비극성 용매로는 아세톤, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 헥산, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소 및 THF 등을 사용할 수도 있다.When the extract used in the composition of the present invention is obtained by treating the raw material with an extraction solvent, various extraction solvents may be used, for example, polar solvents or non-polar solvents may be used. The polar solvent includes (i) water, (ii) alcohol (preferably methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene). glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMF) and (v) dimethyl sulfoxide (DMSO), etc., and non-polar solvents include acetone, acetonitrile, ethyl acetate, methyl acetate, Alkanes, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl Ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride and THF or the like can also be used.
바람직하게는, 본 발명에서 이용되는 추출물은 원물을 착즙하거나, 또는 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출한 것일 수 있지만, 이것으로 제한되는 것은 아니다.Preferably, the extract used in the present invention may be extracted by squeezing raw material or using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent, but this is not limited to
또한, 본 명세서에서 사용되는 용어 '추출물'은 상술한 바와 같이 당업계에서 조추출물(crude extract)로 통용되는 의미를 갖지만, 광의적으로는 추출물을 추가적으로 분획(fractionation)한 분획물도 포함한다. 즉, 원물을 착즙 또는 상술한 추출용매를 이용하여 얻은 추출물뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 것도 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 본 발명의 추출물에 포함되는 것이다.In addition, the term 'extract' used herein has the meaning commonly used in the art as a crude extract (crude extract) as described above, but also includes fractions obtained by further fractionation of the extract in a broad sense. That is, it includes not only extracts obtained by extracting raw materials or using the above-described extraction solvents, but also those obtained by additionally applying a purification process thereto. For example, a fraction obtained by passing the extract through an ultrafiltration membrane having a certain molecular weight cut-off value, separation by various chromatography (made for separation according to size, charge, hydrophobicity or affinity), etc. Fractions obtained through the purification method are also included in the extract of the present invention.
또한, 본 발명의 추출물은 이후 추가적인 과정, 예컨대 여과하거나 농축 또는 건조과정을 수행하여 용매를 제거한 것, 또는 여과, 농축 및 건조를 모두 수행한 것일 수도 있다. 여과는 예를 들어 여과지를 이용하거나 감압여과기를 이용할 수 있으며, 농축은 감압 농축기, 건조는 분무건조 하거나 동결건조법 등을 수행하여 분말 상태의 추출물을 얻을 수도 있다.In addition, the extract of the present invention may be obtained by performing an additional process, such as filtration, concentration or drying, to remove the solvent, or filtration, concentration, and drying. For filtration, for example, filter paper or a vacuum filter may be used, concentration may be performed with a vacuum concentrator, and drying may be performed by spray drying or freeze drying to obtain a powdery extract.
예를 들어, 캐롭 추출물은 캐롭 원료, 예를 들어 캐롭 열매를 분쇄하는 단계; 및 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출 공정을 수행하는 단계를 포함하는 방법에 의하여 제조될 수 있다.For example, carob extract can be obtained by grinding carob raw materials, for example, carob fruit; And it can be prepared by a method comprising the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
본 발명의 일 구현예에 따르면, 상기와 같이 제조한 캐롭 추출물은 아피제닌(apigenin), 시린진산(syringic acid) 및 피니톨(pinitol)을 유효성분으로 포함하는 것일 수 있다. 본 발명의 캐롭 추출물은 아피제닌(apigenin), 시린진산(syringic acid) 및 피니톨(pinitol)을 포함함으로 인하여, 식욕 감소를 일으키지 않으면서, 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료 효과를 갖는 것으로 확인되었다.According to one embodiment of the present invention, the carob extract prepared as above may contain apigenin, syringic acid and pinitol as active ingredients. The carob extract of the present invention contains at least one selected from the group consisting of obesity, diabetes, hyperlipidemia, and fatty liver without reducing appetite due to the inclusion of apigenin, syringic acid, and pinitol. It has been confirmed to have preventive, ameliorative or therapeutic effects on metabolic syndrome.
바람직하게는 본 발명의 캐롭 추출물은 시린진산(syringic acid)을 40 μg/g 내지 200 μg/g의 함량으로 포함하는 것일 수 있다. 보다 구체적으로, 상기 시린진산의 함량은 40 μg/g, 50 μg/g, 60 μg/g, 70 μg/g, 80 μg/g, 90 μg/g, 100 μg/g, 110 μg/g, 120 μg/g, 130 μg/g, 140 μg/g, 150 μg/g, 160 μg/g, 170 μg/g, 180 μg/g, 190 μg/g 또는 200 μg/g일 수 있지만 이에 제한되는 것은 아니며, 40 μg/g 내지 200 μg/g의 범위에 있는 임의의 함량으로 포함될 수 있다. Preferably, the carob extract of the present invention may contain syringic acid in an amount of 40 μg/g to 200 μg/g. More specifically, the content of syringinic acid is 40 μg / g, 50 μg / g, 60 μg / g, 70 μg / g, 80 μg / g, 90 μg / g, 100 μg / g, 110 μg / g, 120 μg/g, 130 μg/g, 140 μg/g, 150 μg/g, 160 μg/g, 170 μg/g, 180 μg/g, 190 μg/g or 200 μg/g, but is limited thereto It is not, and may be included in any amount in the range of 40 μg / g to 200 μg / g.
더 바람직하게는 본 발명의 캐롭 추출물은 피니톨(pinitol) 및 시린진산(syringic acid)을 200~500:1 (피니톨:시린진산)의 중량비로 포함하는 것일 수 있다. 캐롭 추출물 내 피니톨 및 시린진산이 상기 중량비로 포함될 때 다른 중량비로 포함되는 경우와 대비하여 상승효과를 가질 수 있다. 보다 구체적으로, 상기 캐롭 추출물 내 포함된 피니톨 대 시린진산의 중량비는 200:1, 300:1, 400:1 또는 500:1일 수 있지만 이에 제한되는 것은 아니며, 200~500:1 범위에 있는 임의의 중량비로 포함될 수 있다. More preferably, the carob extract of the present invention may include pinitol and syringic acid in a weight ratio of 200 to 500: 1 (pinitol: syringic acid). When the pinitol and syringin acid in the carob extract are included in the above weight ratio, they may have a synergistic effect compared to the case where they are included in other weight ratios. More specifically, the weight ratio of pinitol to syringinic acid contained in the carob extract may be, but is not limited to, 200:1, 300:1, 400:1 or 500:1, and any range in the range of 200 to 500:1 may be included in a weight ratio of
일 구현예에 따르면, 본 발명의 조성물은 캐롭 원료를 분쇄하는 단계; 및 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출 공정을 수행하는 단계를 포함하는 것에 의하여 제조될 수 있다.According to one embodiment, the composition of the present invention comprises the steps of grinding carob raw materials; And it can be prepared by including the step of performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
이와 같이 제조한 본 발명의 조성물은 체중감소, 혈당감소, 혈중 지질감소 및 지방간 개선으로 이루어진 군으로부터 선택되는 1 이상의 효능을 보유하고, 이에 의하여 대사증후군(metabolic　syndrome)의 예방, 개선 또는 치료 효과를 나타낼 수 있다. The composition of the present invention prepared as described above has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction and fatty liver improvement, thereby preventing, improving or treating metabolic syndrome (metabolic syndrome). can indicate
또한, 기존 천연 추출물의 경우 식욕 감소를 통해 체중 및 체지방을 감수시키는 경우가 대부분이지만, 본 발명의 조성물은 식욕 감소를 일으키지 않으면서, 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료 효과를 나타낼 수 있다.In addition, in the case of existing natural extracts, in most cases, weight and body fat are reduced through appetite reduction, but the composition of the present invention does not cause appetite reduction, and at least one metabolism selected from the group consisting of obesity, diabetes, hyperlipidemia, and fatty liver It can show preventive, ameliorative or therapeutic effects of metabolic syndrome.
본 발명은 상기 유효성분을 함유하는 조성물을 포함하고, 약학적으로 허용되는 담체, 부형제 또는 희석제 등을 추가하여 약학적 단위 투여형으로 제형화된 대사증후군의 예방 및 치료를 위한 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention and treatment of metabolic syndrome formulated in a pharmaceutical unit dosage form by adding a pharmaceutically acceptable carrier, excipient or diluent, including a composition containing the active ingredient. .
상기 "약학적으로 허용가능한"이란, 생리학적으로 허용되고 인간에게 투여될 때, 활성성분의 작용을 저해하지 않으며 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 비독성의 조성물을 말한다.The term "pharmaceutically acceptable" means a non-toxic composition that is physiologically acceptable and does not inhibit the action of the active ingredient when administered to humans and does not usually cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions. says
상기 담체, 부형제 또는 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀루로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 포함될 수 있다. 또한 상기 약학적 조성물은 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등을 추가로 포함할 수 있다.Examples of the carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose. , polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers or preservatives.
용어 "약학적으로 유효한 양"이란, 음성 대조군에 비해 그 이상의 반응을 나타내는 양을 말하며 바람직하게는 대사증후군의 예방 및/또는 치료의 효과를 나타내기에 충분한 양을 말한다.The term "pharmaceutically effective amount" refers to an amount that exhibits a greater response than that of the negative control group, and preferably refers to an amount sufficient to exhibit the effect of preventing and/or treating metabolic syndrome.
또한, 본 발명의 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화 될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캡슐, 멸균 주사용액, 멸균 분말의 형태일 수 있다.In addition, the pharmaceutical composition of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The dosage form may be in the form of a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, or sterile powder.
본 발명의 약학적 조성물의 투여 경로로는 이에 한정되는 것은 아니지만, 경구적 또는 비경구적으로 투여될 수 있다. 비경구적 투여 경로로는 예를 들어, 경피, 비강, 복강, 근육, 피하 또는 정맥 등의 여러 가지 경로가 포함될 수 있다. 또한, 본 발명의 약학적 조성물은 대사증후군의 예방 및/또는 치료 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다.The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but may be administered orally or parenterally. Parenteral routes of administration may include, for example, various routes such as transdermal, intranasal, intraperitoneal, intramuscular, subcutaneous or intravenous routes. In addition, the pharmaceutical composition of the present invention can be administered in parallel with known compounds having preventive and/or therapeutic effects on metabolic syndrome.
또 다른 양태로, 본 발명은 상기 조성물 중 어느 하나의 조성물을 포함하는 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition comprising any one of the above compositions.
본 발명의 식품 조성물은 식품, 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health feed) 및 식품 첨가제(food additives) 등의 모든 천연 소재의 가공 형태를 포함한다. 상기 유형의 식품 조성물은 당업계에 공지된 통상적인 방법에 다라 다양한 형태로 제조할 수 있다.The food composition of the present invention includes processed forms of all natural materials such as food, functional food, nutritional supplement, health feed and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
예를 들어, 건강식품으로는 캐롭 추출물 자체를 차, 주스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 또는 분말화하여 섭취할 수 있다. 또한, 본 발명의 캐롭 추출물 이외에, 백작약, 산수유, 가시오가피, 영지버섯, 진피, 초두충, 당귀, 치자, 황기, 맥아, 탱자, 비타민C, 프락토올리고당, 스테비오사이드, 정제수, 말토덱스트린 등을 본 발명의 목적으로 저해하지 않는 범위 내에서 단독으로 또는 혼합하여 더 포함할 수 있으나, 본 발명의 식품 조성물이 추가로 포함할 수 있는 다른 약효 성분 및/또는 첨가제는 상기 예들에 한정되는 것은 아니다.For example, as a health food, carob extract itself can be prepared in the form of tea, juice and drink to be consumed, or granulated, encapsulated, or powdered to be consumed. In addition, in addition to the carob extract of the present invention, white peony, cornus officinalis, cinnamon gapi, ganoderma lucidum, dermis, chinensis, angelica, gardenia, astragalus, malt, tangerine, vitamin C, fructooligosaccharide, stevioside, purified water, maltodextrin, etc. It may be further included alone or in combination within a range that does not interfere with the purpose of the present invention, but other medicinal ingredients and / or additives that may be further included in the food composition of the present invention are not limited to the above examples.
예를 들어, 본 발명에 따른 식품 조성물은 수용성 비타민으로서 티아민(비타민B1), 리보플라빈, 아스코르브산, 니아신, 및 비타민B6를 포함할 수 있고, 지방산으로서 미리스틴산, 팔미트산, 스테아린산, 올레인산, 리놀레인산 등을 포함할 수 있으며, 약산 성분으로서는 글리콜산 및 초산을 포함할 수 있고, 아미노산으로서 트레오닌, 발린, 메티오닌, 이소루신, 루신, 페닐알라닌, 트립토판, 및 리신의 필수아미노산 8종을 비롯하여, 아스파르트산, 세린, 글루탐산, 프롤린, 글리신, 알라닌, 시스테인, 티로신, 히스티딘, 알지닌 등을 포함할 수 있다.For example, the food composition according to the present invention may include thiamin (vitamin B1), riboflavin, ascorbic acid, niacin, and vitamin B6 as water-soluble vitamins, and myristic acid, palmitic acid, stearic acid, oleic acid, It may include linoleic acid, etc., and may include glycolic acid and acetic acid as weak acid components, and 8 essential amino acids of threonine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan, and lysine as amino acids, aspartic acid, serine, glutamic acid, proline, glycine, alanine, cysteine, tyrosine, histidine, arginine, and the like.
본 발명의 조성물은 체중감소, 혈당감소, 혈중 지질감소 및 지방간 개선으로 이루어진 군으로부터 선택되는 1 이상의 효능을 보유하고, 이에 의하여 대사증후군(metabolic　syndrome)의 예방, 개선 또는 치료 효과를 나타낸다.The composition of the present invention has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction and fatty liver improvement, thereby exhibiting an effect of preventing, improving or treating metabolic syndrome.
도 1은 실시예에서 제조한 캐롭 추출물의 사진을 나타낸 것이다(좌: 분무 건조 수행 후 얻어진 분말, 우: 분무 건조 수행 전).Figure 1 shows a photograph of the carob extract prepared in Example (left: powder obtained after spray drying, right: before spray drying).
도 2는 항비만 효과를 검증하기 위하여 마우스 체중의 변화를 평가한 결과를 나타낸 것이다.Figure 2 shows the results of evaluating the change in mouse weight in order to verify the anti-obesity effect.
도 3은 항비만 효과를 검증하기 마우스 체지방 및 복부 지방량의 변화를 실험결과를 나타낸 것이다.Figure 3 shows the experimental results of changes in mouse body fat and abdominal fat to verify the anti-obesity effect.
도 4는 마우스 분변을 통한 콜레스테롤 및 중성 지질 배출량을 측정한 결과를 나타낸 것이다.Figure 4 shows the results of measuring cholesterol and neutral lipid excretion through mouse feces.
도 5는 혈당강하 효과를 평가하기 위하여, 혈중 포도당 농도를 측정한 결과를 나타낸 것이다.5 shows the results of measuring blood glucose concentration in order to evaluate the hypoglycemic effect.
도 6은 마우스 간 조직(hepatic parenchyma) 중 지방간염이 발생된 면적을 측정한 결과를 나타낸 것이다.Figure 6 shows the results of measuring the area where steatohepatitis occurred in mouse liver tissue (hepatic parenchyma).
도 7은 3T3-L1 지방전구세포를 사용한 지방세포 분화 억제 실험에 있어서, 각 시험물질 처리 시 지방 축적율의 변화를 계산하여 나타낸 것이다.7 shows the calculation of the change in fat accumulation rate upon treatment with each test substance in an adipocyte differentiation inhibition experiment using 3T3-L1 preadipocytes.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명 하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.
실시예Example
I. 시험물질제조 및 물질분석I. Test substance preparation and substance analysis
1. 캐롭 추출물의 제조1. Preparation of carob extract
캐롭(CR; Carob)을 분쇄한 후 후 10배수의 30% 에탄올(에탄올:물=30:70, V/V)을 용매로 하여, 70℃에서 6시간동안 추출하였다. 그 후, 여과하여 60~65℃에서 20~25brix 가 되도록 농축한 다음, 60~70℃에서 감압을 통해 건조한 후 milling 과 sizing 하여 연 노랑색 분말(light yellow powders)로서 캐롭 추출물을 제조하였다. Carob (CR; Carob) was pulverized, and then extracted with 10 folds of 30% ethanol (ethanol:water = 30:70, V/V) as a solvent at 70°C for 6 hours. Then, it was filtered and concentrated to 20-25 brix at 60-65 ° C, dried under reduced pressure at 60-70 ° C, and then milled and sized to prepare carob extract as light yellow powders.
2. 물질 분석2. Material analysis
고속액체크로마토그래피 방법을 이용하여 상기 제조한 캐롭 추출물 내 성분을 분리한 결과, 상기 캐롭 추출물은 아피제닌(apigenin), 시린진산(syringic acid) 및 피니톨(pinitol)을 함유하는 것으로 확인되었다. As a result of separating the components in the prepared carob extract using a high performance liquid chromatography method, it was confirmed that the carob extract contained apigenin, syringic acid and pinitol.
II. 효능 평가II. Efficacy evaluation
1. 동물 모델 확립1. Animal Model Establishment
기존에 비만 치료제의 개발을 위한 다양한 실험동물 모델이 개발되었으나, 대부분 너무 심각한 비만이 유발되어 이미 확립된 비만증에 대한 치료제의 약효 평가에 적당할 뿐, 예방 또는 기능성 식품 개발에 부적당한 것으로 평가되었다. Various experimental animal models for the development of anti-obesity drugs have been developed in the past, but most of them induce severe obesity, so they are only suitable for evaluating the efficacy of drugs for obesity that have already been established, but are evaluated as inappropriate for the development of preventive or functional foods.
본 발명자들은 고지방 사료(high fat diet, HFD) 공급에 의해 설치류인 마우스에서도 비만이 발생함을 확인하였다. 즉, HFD 공급으로 ICR mice 에서 사람의 비만 발생과 유사하고, 기능성 식품의 약효 평가에 적당한 정도의 비만이 유도될 수 있음을 확인하여 HFD 를 이용한 실험동물 모델을 확립하였다.The present inventors have confirmed that obesity occurs in mice, which are rodents, by supplying a high fat diet (HFD). In other words, it was confirmed that HFD feeding can induce obesity similar to human obesity in ICR mice, and that an appropriate degree of obesity can be induced in the evaluation of the efficacy of functional foods, and an experimental animal model using HFD was established.
구체적으로 총 200마리의 6주령 암컷 ICR 마우스 [OrientBio, Seungnam, Korea]를 7일간 실험실 환경에 순응시킨 후, 1 주일간 HFD에 적응시킨 다음 일정한 체중 증가를 나타내는 실험동물만 선별하여 실험에 사용하였다. 모든 실험동물은 대구한의대학교 실험동물윤리위원회의 사전승인 하에 동물실험윤리 기준에 따라 취급하였다. 정상 대조군에서는 일반 NFD(Normal fat diet)를 동일한 방법으로 공급하였다.Specifically, a total of 200 6-week-old female ICR mice [OrientBio, Seungnam, Korea] were acclimatized to the laboratory environment for 7 days and then to HFD for 1 week. All experimental animals were treated according to the animal experimentation ethics standards under the prior approval of the Laboratory Animal Ethics Committee of Daegu Haany University. In the normal control group, NFD (Normal Fat Diet) was supplied in the same way.
실험물질로는 상기 제조한 캐롭 추출물(CR)을 사용하였다. 실험물질 투여 용량은 200 mg/kg으로 설정하였고, 이를 위하여 캐롭 추출물을 20 mg/ml의 농도로 멸균 증류수에 용해시켜, 마우스의 일반 경구투여 volume 인 10 ml/kg으로 매일 1 회씩 84일간 강제 경구투여 하였다. As a test substance, the carob extract (CR) prepared above was used. The dose of the test substance was set at 200 mg/kg. To this end, the carob extract was dissolved in sterile distilled water at a concentration of 20 mg/ml, and forced orally once daily for 84 days at 10 ml/kg, which is the normal oral administration volume of mice. administered.
대조약물로 사용한 metformin 의 투여 용량은 이전의 참고문헌을 바탕으로 250 mg/kg으로 설정하였다. Metformin 역시 25 mg/ml 농도로 멸균 증류수에 용해시킨 다음 10 ml/kg의 용량(250 mg/kg)으로 매일 1 회씩 84일간 경구투여 하였다. The dose of metformin used as a control drug was set at 250 mg/kg based on previous references. Metformin was also dissolved in sterile distilled water at a concentration of 25 mg/ml and then orally administered at a dose of 10 ml/kg (250 mg/kg) once daily for 84 days.
정상 및 HFD 대조군에서는 동일한 투여 및 보정 스트레스를 가하기 위하여 실험물질 대신 멸균 증류수만 동일한 방법으로 동일한 기간 동안 강제 경구 투여하였다.In the normal and HFD control groups, only sterilized distilled water was administered orally for the same period of time in the same manner instead of the test substance in order to apply the same administration and correction stress.
2. 체중 및 평균 사료 섭취량의 변화2. Changes in body weight and average feed intake
항비만 효과를 검증하기 위하여 체중의 변화를 평가하였고 실험결과를 도 2에 나타내었다.In order to verify the anti-obesity effect, changes in body weight were evaluated, and the experimental results are shown in FIG. 2 .
실험결과, HFD 대조군에서는 정상 대조군(NFD)에 비해 1주일간의 HFD 적응기간 동안 유의성 있는 증가를 나타내었으며, 84일간의 실험 물질 투여기간 동안에 현저한 체중 증가를 나타내었다. 반면에, metformin 250 mg/kg (양성 대조군) 및 캐롭 추출물 200 mg/kg (시험군)을 투여한 경우, 각각 HFD 대조군에 비해 현저한 체중 감소가 인정되었다. As a result of the experiment, the HFD control group showed a significant increase during the 1-week HFD adaptation period compared to the normal control group (NFD), and showed a significant increase in body weight during the 84-day test material administration period. On the other hand, when metformin 250 mg/kg (positive control group) and carob extract 200 mg/kg (test group) were administered, significant weight loss was observed compared to the HFD control group.
평균 사료 섭취량은 HFD 대조군의 경우, 정상 대조군에 비해 -10.69%의 변화를 나타내었으나, metformin 250 mg/kg 및 캐롭 추출물 200 mg/kg 투여군에서는 HFD 대조군에 비해 각각 -1.53% 및 -0.78%의 변화를 나타내어 식욕 감소를 일으키지 않음이 확인되었다.Mean feed intake in the HFD control group showed a change of -10.69% compared to the normal control group, but in the metformin 250 mg/kg and carob extract 200 mg/kg groups, the change was -1.53% and -0.78%, respectively, compared to the HFD control group. It was confirmed that it did not cause a decrease in appetite.
3. 지방 축적 억제 및 배출 효과 확인3. Confirmation of fat accumulation suppression and discharge effect
항비만 효과를 검증하기 위하여 84일간의 투여기간 후 체지방 및 복부 지방량의 변화를 실험결과를 도 3에 나타내었다. 실험결과, HFD 대조군에서는 정상 대조군에 비해 현저한 체지방 및 복부 축적 지방량의 증가가 각각 인정된 반면, metformin 250 mg/kg 및 캐롭 추출물 200 mg/kg 투여군에서는 HFD 대조군에 비해 유의성 있는 체지방 및 복부 축적 지방량의 감소를 나타내는 것으로 확인되었다(도 3).In order to verify the anti-obesity effect, the experimental results of changes in body fat and abdominal fat after an administration period of 84 days are shown in FIG. 3. As a result of the experiment, in the HFD control group, significant increases in body fat and abdominal fat accumulation were recognized compared to the normal control group, whereas in the metformin 250 mg/kg and carob extract 200 mg/kg administration group, there was a significant increase in body fat and abdominal fat accumulation compared to the HFD control group. It was found to show a decrease (Fig. 3).
또한 지방 배출 효과를 확인하기 위하여 84일간의 투여기간 동안 분변을 통한 콜레스테롤 및 중성 지질 배출량을 측정한 후 그 평균값을 계산하여 도 4에 나타내었다. 실험결과, HFD 대조군에서의 지방 배출량은 정상 대조군(NFD)과 비교하여 유의한 차이가 관찰되지 않은 반면에, metformin 250 mg/kg 및 캐롭 추출물 200 mg/kg 투여군에서는 현저한 콜레스테롤 및 중성 지질 배출 활성이 확인되었다(도 4).In addition, in order to confirm the fat excretion effect, cholesterol and neutral lipid excretion through feces were measured during the 84-day administration period, and the average value was calculated and shown in FIG. As a result of the experiment, no significant difference was observed in fat excretion in the HFD control group compared to the normal control group (NFD), whereas significant cholesterol and neutral lipid excretion activities were observed in the metformin 250 mg/kg and carob extract 200 mg/kg administration groups. confirmed (FIG. 4).
4. 고지혈증 개선 활성 평가4. Evaluation of hyperlipidemia improvement activity
고지혈증 개선 활성을 평가하기 위하여, 84일간의 실험 기간 후 마우스 혈중 콜레스테롤 및 중성 지질, LDL & HDL 콜레스테롤 함량의 변화를 측정하였다. 측정값은 8마리 마우스에 대해 평균 ± SD으로 표시하였으며, 그 결과를 하기 표 1에 나타내었다.In order to evaluate the hyperlipidemia-improving activity, changes in mouse blood cholesterol, neutral lipids, and LDL & HDL cholesterol contents were measured after an 84-day experimental period. Measurement values were expressed as mean ± SD for 8 mice, and the results are shown in Table 1 below.
Figure PCTKR2022014570-appb-img-000001
Figure PCTKR2022014570-appb-img-000001
상기 표 1에서 확인되는 바와 같이, 캐롭 추출물에서 200 mg/kg 투여군은 혈중 콜레스테롤 및 중성 지질, LDL & HDL 콜레스테롤 수치 모두에서 우수한 고지혈증 개선 활성을 갖는 것으로 확인되었다.As confirmed in Table 1, the 200 mg/kg administration group in the carob extract was confirmed to have excellent hyperlipidemia-improving activity in both blood cholesterol and neutral lipids, LDL & HDL cholesterol levels.
5. 혈중 포도당 농도 평가5. Assessment of blood glucose concentration
혈당강하 효과를 평가하기 위하여, 혈중 포도당 농도를 측정하고 그 결과를 도 5에 나타내었다. 실험결과, HFD 대조군에서는 정상 대조군에 비해 현저한 혈당 증가가 확인된 반면에, metformin 250 mg/kg 및 캐롭 추출물 200 mg/kg 투여군에서는 HFD 대조군에 비해 유의성 있는 혈당 개선이 관찰되어, 혈당 개선을 통한 당뇨 개선 활성을 나타내는 것으로 확인되었다(도 5).To evaluate the hypoglycemic effect, blood glucose concentration was measured and the results are shown in FIG. 5 . As a result of the experiment, a significant increase in blood glucose was confirmed in the HFD control group compared to the normal control group, whereas a significant improvement in blood glucose was observed in the group administered with metformin 250 mg/kg and carob extract 200 mg/kg compared to the HFD control group. It was confirmed to show improvement activity (FIG. 5).
6. 간 보호 효과 평가6. Evaluation of liver protective effect
간 보호 효과를 평가하기 위하여, 84일간의 실험 기간 후 마우스 혈중 aspartate aminotransferase (AST), alanine aminotransferase (ALT), 및 gamma-glutamyltransferase (GGT) 함량의 변화를 측정하였다. 측정값은 8마리 마우스에 대해 평균 ± SD으로 표시하였으며, 그 결과를 하기 표 2에 나타내었다.To evaluate the hepatoprotective effect, changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) contents in mouse blood were measured after the 84-day experimental period. Measurement values were expressed as mean ± SD for 8 mice, and the results are shown in Table 2 below.
Figure PCTKR2022014570-appb-img-000002
Figure PCTKR2022014570-appb-img-000002
7. 지방간 개선 활성 확인 7. Confirmation of fatty liver improvement activity
간에 중성지방(triglyceride; TG)이 과도하게 축적되는 비알코올성 지방간질환(nonalcoholic fatty liver disease, 이하 NAFLD)은 비만, 인슐린저항성, 2형 당뇨병, 고혈압, 고지혈증 등 대사증후군(metabolic syndrome)과 관련이 있으며, 지방간염(Liver steatohepatitis)을 수반하기도 한다.Nonalcoholic fatty liver disease (NAFLD), in which triglyceride (TG) is excessively accumulated in the liver, is associated with metabolic syndrome such as obesity, insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia. It may also accompany liver steatohepatitis.
84일간의 실험 기간 후 마우스를 희생시키고 조직 검사를 통하여 마우스 간 조직(hepatic parenchyma) 중 지방간염이 발생된 면적을 측정하여 그 결과를 도 6에 나타내었다. 실험결과, HFD 대조군에서는 정상 대조군에 비해 현저하게 높은 지방간염이 관찰되었다. 반면에, metformin 250 mg/kg 및 캐롭 추출물 200 mg/kg 투여군에서는 HFD 대조군에 비해 유의성 있는 지방간염의 개선 결과를 나타내어 지방간 개선 활성을 갖는 것으로 확인되었다(도 6).After the experimental period of 84 days, the mouse was sacrificed and the area where steatohepatitis occurred in the mouse liver tissue (hepatic parenchyma) was measured through a histological examination, and the results are shown in FIG. 6 . As a result of the experiment, significantly higher steatohepatitis was observed in the HFD control group than in the normal control group. On the other hand, in the group administered with 250 mg/kg of metformin and 200 mg/kg of carob extract, it was confirmed to have a fatty liver improving activity by showing significant improvement in steatohepatitis compared to the HFD control group (FIG. 6).
8. 캐롭 추출물 내 피니톨 및 시린진산 중량비에 따른 효과 확인8. Confirmation of the effect according to the weight ratio of pinitol and syringic acid in carob extract
캐롭 추출물 내 포함된 피니톨 및 시린진산 중량비에 따른 효과를 확인하기 위해 실험물질 처리 후 3T3-L1 지방전구세포의 분화 억제 활성을 측정하였다. 대조군으로는 metformin를 사용하였고, 실험물질로는 상기 실시예 I에서 제조한 캐롭 추출물(CR)에 피니톨을 첨가하여 캐롭 추출물 내 포함된 피니톨 및 시린진산 중량비를 하기 표 3과 같이 조정한 것을 사용하였다. 각 실험물질 처리 용량은 100 μg/ml 로 동일하게 설정하였다. In order to confirm the effect according to the weight ratio of pinitol and syringic acid contained in the carob extract, the differentiation inhibitory activity of 3T3-L1 preadipocytes was measured after treatment with the test substance. As a control, metformin was used, and as an experimental substance, pinitol was added to the carob extract (CR) prepared in Example I to adjust the weight ratio of pinitol and syringin acid contained in the carob extract as shown in Table 3 below. . The treatment capacity of each test substance was equally set at 100 μg/ml.
시료sample 처리 용량 processing capacity
대조군(control)control 100 μg/ml100 µg/ml
피니톨pinitol 100 μg/ml100 µg/ml
시린진산 syringic acid 100 μg/ml100 µg/ml
CR - 상기 실시예 I에서 제조한 캐롭추출물CR - carob extract prepared in Example I above 100 μg/ml100 µg/ml
CR(100:1) - 피니톨:시린진산 중량비가 100:1로 조정된 캐롭 추출물CR (100:1) - carob extract adjusted to a pinitol:syringic acid weight ratio of 100:1 100 μg/ml100 µg/ml
CR(200:1) - 피니톨:시린진산 중량비가 200:1로 조정된 캐롭 추출물CR(200:1) - carob extract adjusted to pinitol:syringic acid weight ratio of 200:1 100 μg/ml100 µg/ml
CR(500:1) - 피니톨:시린진산 중량비가 500:1로 조정된 캐롭 추출물CR(500:1) - carob extract adjusted to pinitol:syringic acid weight ratio of 500:1 100 μg/ml100 µg/ml
CR(1000:1) - 피니톨:시린진산 중량비가 1000:1로 조정된 캐롭 추출물CR(1000:1) - carob extract adjusted to 1000:1 weight ratio of pinitol:syringic acid 100 μg/ml100 µg/ml
구체적으로 배양 및 분화 배지는 Dulbecco's modified Eagle's medium high glucose(DMEM: Invitrogen, Carlsbad, CA, USA)에 10% calf serum, antibiotics를 첨가하여 5% CO2, 37℃ 인큐베이터에서 배양하여 세포가 confluent 상태가 되면 trypsin/ EDTA를 처리하여 세포를 원심분리(L-70, Bekman Coulter, Fullerton, CA, USA)하여 세포를 모아서 3Х105 cells/well의 밀도로 6 well에 분주한 후 100% confluency 상태에서 48시간 방치 후 DMEM에 10% BCS와 23 mg/mL IBMX(Sigma-Aldrich, Chem. Co., St. Louis, MO, USA), 5 mg/mL insulin(Sigma-Aldrich), 1 mM dexamethasone(Sigma-Aldrich)이 첨가된 배지(MDI)를 처리하여 분화를 48시간 동안 유도하였다. 시험물질의 처리는 100 μg/ml의 농도로 분화유도 배지 첨가 시점부터 같이 처리하였으며, 9일 동안 분화시킨 후 배지를 제거하고 phosphate buffered saline(PBS)로 세척하고 10% formaldehyde 용액으로 세포를 고정시켰다. 다시 PBS로 세척 후, Oil red O 용 액을 첨가하여 30분간 실온에서 염색하고, Oil red O 용액을 제 거한 후 증류수로 세척하여 건조시킨 다음 위상차 현미경을 이 용하여 관찰하고 100% isopropyl alcohol로 염색된 지방구를 용해하여 510 nm에서 흡광도를 측정하였다. 대조군 처리 시 얻어진 값을 100%로 하고, 이에 대비한 각 시험물질 처리시 측정된 지방 축적율을 계산하여 그 결과를 도 7에 나타내었다.Specifically, for culture and differentiation medium, Dulbecco's modified Eagle's medium high glucose (DMEM: Invitrogen, Carlsbad, CA, USA) was added with 10% calf serum and antibiotics, and cultured in a 5% CO 2 , 37°C incubator so that the cells were confluent. After treatment with trypsin/EDTA, the cells are centrifuged (L-70, Bekman Coulter, Fullerton, CA, USA) to collect the cells and dispensed into 6 wells at a density of 3Х10 5 cells/well for 48 hours at 100% confluency. After standing, DMEM contained 10% BCS, 23 mg/mL IBMX (Sigma-Aldrich, Chem. Co., St. Louis, MO, USA), 5 mg/mL insulin (Sigma-Aldrich), and 1 mM dexamethasone (Sigma-Aldrich). ) was added to the medium (MDI) to induce differentiation for 48 hours. The test substance was treated at a concentration of 100 μg/ml from the time of addition of the differentiation induction medium, and after differentiation for 9 days, the medium was removed, washed with phosphate buffered saline (PBS), and cells were fixed with 10% formaldehyde solution. . After washing again with PBS, dyeing was performed at room temperature by adding Oil red O solution for 30 minutes, removing the Oil red O solution, washing with distilled water, drying, observing using a phase contrast microscope, and staining with 100% isopropyl alcohol. Fat globules were dissolved and absorbance was measured at 510 nm. The value obtained during the treatment of the control group was set as 100%, and the fat accumulation rate measured during the treatment of each test substance was calculated, and the results are shown in FIG. 7 .
실험결과, 처리량이 100 μg/ml의 농도로 동일하였음에도 CR(200:1) 및 CR(500:1) 처리군에서 현저하게 낮은 지방 축적율이 확인되어 상기 중량비에서 상승 효과가 있는 것이 확인되었다(도 7).As a result of the experiment, even though the treatment amount was the same at a concentration of 100 μg / ml, a remarkably low fat accumulation rate was confirmed in the CR (200: 1) and CR (500: 1) treatment groups, and it was confirmed that there was a synergistic effect in the weight ratio ( Fig. 7).

Claims (12)

  1. 비만, 당뇨, 고지혈증 및 지방간으로 이루어진 군으로부터 선택되는 1 이상의 대사증후군(metabolic syndrome)의 예방, 개선 또는 치료를 위한 조성물로서, 캐롭 추출물을 유효성분으로 포함하는 것을 특징으로 하는 조성물.A composition for preventing, improving or treating at least one metabolic syndrome selected from the group consisting of obesity, diabetes, hyperlipidemia and fatty liver, comprising a carob extract as an active ingredient.
  2. 제1항에 있어서, 상기 캐롭 추출물은 아피제닌(apigenin), 시린진산(syringic acid) 및/또는 피니톨(pinitol)을 유효성분으로 포함하는 것인 조성물.The composition according to claim 1, wherein the carob extract contains apigenin, syringic acid and/or pinitol as active ingredients.
  3. 제1항에 있어서, 상기 캐롭 추출물은 시린진산(syringic acid)을 40 μg/g 내지 200 μg/g의 함량으로 포함하는 것인 조성물. The composition of claim 1, wherein the carob extract contains syringic acid in an amount of 40 μg/g to 200 μg/g.
  4. 제1항에 있어서, 상기 캐롭 추출물은 피니톨(pinitol) 및 시린진산(syringic acid)을 200~500:1 (피니톨:시린진산)의 중량비로 포함하는 것인 조성물. The composition of claim 1, wherein the carob extract contains pinitol and syringic acid in a weight ratio of 200 to 500: 1 (pinitol: syringic acid).
  5. 제1항에 있어서, 상기 캐롭 추출물은 캐롭 열매 추출물인 것을 특징으로 하는 조성물.The composition according to claim 1, wherein the carob extract is a carob fruit extract.
  6. 제1항에 있어서, 상기 캐롭 추출물은 물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출한 것을 특징으로 하는 조성물.The composition according to claim 1, wherein the carob extract is extracted using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
  7. 제 1항에 있어서, 상기 조성물은 체중감소, 혈당감소, 혈중 지질감소 및 지방간 개선으로 이루어진 군으로부터 선택되는 1 이상의 효과를 갖는 것을 특징으로 하는 조성물.The composition according to claim 1, wherein the composition has at least one effect selected from the group consisting of weight loss, blood sugar reduction, blood lipid reduction and fatty liver improvement.
  8. 제1항에 있어서, 상기 조성물은 식욕 감소를 일으키지 않으면서, 체중감소, 체지방 감소 및 복부 지방 감소로 이루어진 군으로부터 선택되는 1 이상의 효과를 갖는 것을 특징으로 하는 조성물.The composition according to claim 1, wherein the composition has at least one effect selected from the group consisting of weight loss, body fat reduction, and abdominal fat reduction without causing a decrease in appetite.
  9. 제1항 내지 제8항 중 어느 하나의 항에 있어서, 상기 조성물은 식품 조성물인 것을 특징으로 하는 조성물.9. The composition according to any one of claims 1 to 8, wherein the composition is a food composition.
  10. 제1항 내지 제8항 중 어느 하나의 항에 있어서, 상기 조성물은 약학 조성물인 것을 특징으로 하는 조성물.9. The composition according to any one of claims 1 to 8, wherein the composition is a pharmaceutical composition.
  11. 제1항 내지 제8항 중 어느 하나의 항에 따른 조성물을 포함하는 건강기능식품.A health functional food comprising the composition according to any one of claims 1 to 8.
  12. 캐롭 원료를 분쇄하는 단계; 및Grinding carob raw materials; and
    물, 탄소수가 1 내지 4의 저급 알코올 및 이들의 혼합물로 이루어진 군 중에서 선택된 어느 하나를 추출 용매로 사용하여 추출 공정을 수행하는 단계Performing an extraction process using any one selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixtures thereof as an extraction solvent.
    를 포함하는 제1항 내지 제8항 중 어느 하나의 항에 따른 조성물의 제조방법.A method for producing a composition according to any one of claims 1 to 8 comprising a.
PCT/KR2022/014570 2021-10-01 2022-09-28 Composition for preventing, alleviating or treating metabolic syndrome, comprising carob extract WO2023055079A1 (en)

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KR20040052794A (en) * 2004-05-04 2004-06-23 뉴트라팜주식회사 The specialty grains with lowering blood glucose and/or cholesterol levels and their manufacturing method
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